All compounds evaluated in this study were purchased from Sigma-Aldrich Co., Ltd. The melting point for the compounds was determined on an Electro thermal (900 model). ¹H and ¹³C NMR (nuclear magnetic resonance) spectra were recorded on a Varian VXR-300/5 FT NMR spectrometer at 300 and 75.4 MHz (megahertz) in CDCl₃ (deuterated chloform) using TMS (tetramethylsilane) as internal standard. EIMS (electron impact mass spectroscopy) spectra were obtained with a Finnigan Trace Gas Chromatography Polaris Q Spectrometer. Elementary analysis data were acquired from a Perkin Elmer Ser. II CHNS/0 2400 elemental analyzer.

All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal care and use Committee of University Autonomous of Campeche (No. PI-420/12) and were in accordance with the guide for the care and use of laboratory animals [17] . Male Wistar rats; weighing 200 - 250 g were obtained from University Autonomous of Campeche.

All drugs were dissolved in methanol and different dilutions were obtained using Krebs-Henseleit solution (≤ 0.01%, v/v).

Briefly, the male rat (200 - 250 g) was anesthetized by injecting them with pentobarbital at a dose rate of 50 mg/Kg body weight. Then the chest was opened, and a loose ligature passed through the ascending aorta. The heart was then rapidly removed and immersed in ice cold physiologic saline solution. The heart was trimmed of non-cardiac tissue and retrograde perfused via a non-circulating perfusion system at a constant flow rate. The perfusion medium was the Krebs-Henseleit solution (pH = 7.4, 37˚C) composed of (mmol); 117.8 NaCl; 6 KCl; 1.75 CaCl₂; 1.2 NaH₂PO₄; 1.2 MgSO₄; 24.2 NaHCO₃; 5 glucose and 5 sodium pyruvate. The solution was actively bubbled with a mixture of O₂/CO₂ (95:5/5 %). The coronary flow was adjusted with a variable speed peristaltic pump. An initial perfusion rate of 15 ml/min for 5 min was followed by a 15 min equilibration period at a perfusion rate of 10 ml/min. All experimental measurements were done after this equilibration period.

Evaluation of measurements of perfusion pressure changes induced by drugs administration in this study were assessed using a pressure transducer connected to the chamber where the hearts were mounted and the results entered into a computerized data capture system (Biopac).

Contractile function was assessed by measuring left ventricular developed pressure (LV/dP), using a saline- filled latex balloon (0.01 mm, diameter) inserted into the left ventricle via the left atrium [18] . The latex balloon was bound to cannula which was linked to pressure transducer that was connected with the MP100 data acquisition system.

The hearts (n = 9) were perfused with compound 5 (1 mmol) and vehicle (control) for 2, 5, or 30 minutes. After the appropriate period of infusion, atrial tissue was removed, and the ventricles were immediately frozen with liquid nitrogen and stored at 270˚C until assayed. Tissue samples were homogenized with 6% trichloroacetic acid at 4˚C to give a 10% (w/v) homogenate, followed by centrifugation at 2000 rpm (Hettich Zentrifugen, EBA-270) for 15 minutes. Then supernatants were collected and washed with water:diethyl ether (5:1 v/v) five times. The extracts were lyophilized and processed for the measurement of cAMP content by use of a standard ¹²⁵I radioimmunoassay kit supplied by Amersham International [21] .

The obtained values are expressed as average ± SE, using each heart (n = 9) as its own control. The data obtained were put under Analysis of Variance (ANOVA) with the Bonferroni correction factor using the SPSS 12.0 program [22] . The differences were considered significant when p was ≤0.05.

There are several procedures for the synthesis of aromatic-derivatives [23] - [25] ; nevertheless, expensive reagents and special conditions are required; therefore, in this study a new naphthalene-prazosin derivative was synthesized. It is noteworthy that prazosin was used because in their chemical structure has specific functional groups that can interact with molecules such as ethylenediamine to form a spacer arm; this compound is used to couplethearomatic derivative. Therefore, in this study the first stage was achieved by the reaction of prazosin with ethylenediamine to form the compound 3 (C₂₁H₂₇N₇O₃) using as boric acid as catalyst (Figure 1). The structure of compound 3 was confirmed using NMR spectroscopy (Table 1 and Table 2). The ¹H NMR spectrum of the compound 3 shows signals at 3.04 and 3.70 ppm for methylene groups bound to both amino groups; at 3.56 - 3.64, 3.88 and 4.00 ppm for pyrimidine ring; at 3.90 and 3.96 ppm for both methoxy groups; at 6.36, 7.20 and 7.76 ppm for protons involved in furan ring; at 6.70 for both amino groups; at 6.76 and 7.70 ppm for phenyl group. The ¹³C NMR spectra displays chemical shifts at 40.50 and 55.40 ppm for both methylene groups; at 45.78, 47.60 and 158.60 - 161.18 ppm for pyrimidine ring; at 55.50 and 55.90 ppm for both methoxy groups; at 103.00 - 105.18 and 145.17 - 154.33 ppm for phenyl group; at 113.00 - 126.92 and 145.17 - 154.33 ppm for protons involved in furan ring; at 144.50 ppm for imino group. Finally, the presence of the naphthalene derivativewas further confirmed from mass spectrum which showed a molecular ion at m/z 425.20.

The second stage (Figure 2) was achieved by the synthesis of Compound 5 (C₄₃H₃₉N₇O₅) by the reaction of compound 3 with 2-hydroxy-1-naphthaldehyde using boric acid as catalyst. The structure of compound 3 was confirmed using NMR spectroscopy (Table 3 and Table 4). The ¹H NMR spectrum of the compound 3 shows signals at 3.50, 3.60, 3.88 and 4.00 ppm for pyrimidine ring; at 3.58 and 3.70 ppm for methylene groups bound to both amino groups; at 3.80 and 3.90 ppm for both methoxy groups; at 6.38, 7.20 and 7.72 for furan ring; at 6.68 - 6.90, 7.46 - 7.68 and 7.78 - 8.50 ppm for phenyl groups; at 8.70 - 8.90 ppm for imino groups; at 14.18 ppm for both hydroxyl groups. The ¹³C NMR spectra displays chemical shifts at 45.80 - 47.60, 162.39 and 162.84 ppm for pyrimidine ring; at 50.08 - 52.90 for methylene groups bound to both amino groups; at 55.50 and 5.90 ppm for both methoxy groups; at 113.18, 126.92 and 145.40 ppm for furan ring; at 104.40 - 108.10, 120.56 -

126.20, 127.00 - 137.00, 151.90 - 159.82 and 162.84 ppm for phenyl groups; at 140.50, 163.50 and 165.00 ppm for imino groups. Finally, the presence of the compound 5was further confirmed from mass spectrum which showed a molecular ion at m/z 733.30.

Several drugs have been used to treat the ischemia/reperfusion injury resulting from myocardial ischemia [26] - [28] ; nevertheless, there is scarce information about the effects naphthalene derivatives on this phenomenon. Therefore, in this study the activity of a naphthalene-proposing derivative on the ischemia/reperfusion injury was evaluated.

In order to evaluate the activity of the naphthalene-prazosin derivative (compound 5) on injury by ischaemia/reperfusion an isolated heart model was used. The results showed that the compound 5 reduced infarct size (expressed as a percentage of the area at risk) compared with vehicle-treated hearts (Figure 3). This phenomenon induced by the compound 5 could be by activation of some structure biological (p.e. ionic channels or specific receptors) involved in the endothelium of coronary artery such as happening with other compounds [29] or by the influence exerted by the compound 5 on blood pressure which could result reduction in the infarct size, and decrease the myocardial injury after ischemia-reperfusion; it is important to mention that this effect is similar to other reports for other type of drugs [30] .

Analyzing this hypothesis, the activity induced by the naphthalene derivative on blood vessel capacity and coronary resistance; translated as changes in perfusion pressure was evaluated in an isolated rat heart model. The results indicate that the naphthalene derivative significantly increases the perfusion pressure over time (3 - 18 min) compared with control conditions (Figure 4). Analyzing these data and considering that part of structure as well as the functional groups involved in the chemical structure of compound 5 could be responsible for the activity exerted on perfusion pressure; in this study, the compounds 3, 4 and prazosin were used such pharmacological tool.

The results showed that perfusion pressure was decreased by prazosin; however in presence of the compound 3 and 4 at a dose of 0.001 nM the perfusion pressure was not affected. Therefore these data confirm that functional groups different involved in the compound 5 are the responsible of the activity exerted on perfusion pressure, which could result in changes in coronary resistance. To evaluate this hypothesis, the effects induced by prazosin and the compounds 3, 4 and 5 at a dose of 0.001 nM on coronary resistance were evaluated (Figure 5). The results showed that coronary resistance in presence of the compound 5 was higher (p = 0.05) in comparison with prazosin, compounds 3 and 4 at dose of 0.001 nM and control conditions.

On the other hand, in the search of molecular mechanism of activity induced by the compound 5 on perfusion pressure, in this study was analyzed a report, which indicates that some naphthalene-derivatives can induce changes on blood pressure via adrenergic system [10] . To evaluate these hypotheses, and analyzing the reports which indicate that prazosin interacts with α₁-adrenergic receptors [13] ; in this study the activity exerted by the compound 5 on left ventricular pressure in the absence or presence of prazosin was evaluated (Figure 6). The results showed that the compound 5 increases the left ventricular pressure at dose of 0.001 to 100 nM and this effect was not inhibited by prazosin at dose of 1 nM. Also, was evaluated the effect induced by the compound 5 on left ventricular pressure in presence of metoprolol, to test whether the activity of aromatic derivative is viaβ₁-adrenergic receptors. All these data indicate that the molecular mechanism involved in the effects exerted by the compound 5 on left ventricular pressure was not through adrenergic activity.

Analyzing other reports which indicate that some drugs may induce its effect on left ventricular pressure via prostaglandins synthesis [31] ; the activity exerted by the compound 5 on left ventricular pressure in the absence or presence of indomethacin [1 nM] was analyzed to evaluate the possibility that the activities exerted by the naphthalene derivative involve stimulation and secretion of prostaglandins. The results (Figure 7) showed that the compound 5 increased the left ventricular pressure at dose of 0.001 to 100 nM and this effect was not blocked in presence of indomethacin. These data indicate that activity exerted by the compound 5 on left ventricular pressure was not via prostanoids synthesis and secretion.

On the other hand, other results showed that the compound 5 (Figure 8) increases the left ventricular pressure in a dose dependent manner [0.001 to 100 nM]; however this effect was blocked in presence of nifedipine at a

dose of 1 nM. These results suggest that activity exerted by the naphthalene derivative was via calcium channel type L activation. This coincides with previous studies which indicate that some compounds [32] exert their activity on left ventricular pressure through calcium channels activation

Analyzing these data and other report [33] which indicates that levosimendam exert effect on the ische-

mia/reperfusion injury via changes in the concentration of calcium intracellular and cAMP; in this study, was evaluated the activity induced by the compound 5on in cAMP levels using isoproterenol as pharmacological tool. The results (Figure 8) indicate that the isoproterenol increases cAMP levels (3 to 12 minutes) compared to compound 5andcontrol conditions; however, it is important to mention that after 15 to 18minutesthe effect of isoproterenol decreased significantly; these phenomenon is similar a to other studies previously reported for isoproterenol [21] [34] . In addition, the compound 5 was not exerts effects on cAMP levels. All these data indicate; 1) The effect exerted by the isproterenolis mediated by cAMP in 3 to 12 minutes; 2) The effect of compound 5 is independent of cAMP levels.